Although children who take proton pump inhibitors (PPIs) to treat gastroesophageal reflux disease (GERD) have a six times greater risk of gastroenteritis and a twelve times greater risk of pneumonia than healthy controls, the mechanism driving these risks is unknown. Understanding this mechanism is critical because PPIs are one of the most prescribed classes of medications in children and adults and this understanding will enable clinicians to identify and modify the medical treatment of patients at high risk for pneumonia or gastroenteritis. The central hypothesis of the proposed study is that PPIs promote a non-acidic gastric environment in which gastric microflora are altered, and those alterations result in gastrointestinal-wide changes to microflora that increase risk of infection. The rationale for the proposed study is that, despite the widespread belief that PPIs are safe and effective and a more than 400% increase in the frequency of pediatric PPI prescriptions dispensed during the last 7 years, evidence shows that almost 50% of children who take PPIs develop an infectious complication. From a public health perspective, understanding the mechanism behind the high complication rate is critical in order to reduce avoidable infections. Using advanced culturing, 16S deep sequencing, and viral metagenomics, the immediate goals of the proposed study are: (1) to identify the gastric, oropharyngeal, and stool microflora changes in children who take PPIs; (2) to determine the PPI- associated microflora changes that predict pneumonia and gastroenteritis risk; and (3) to identify potential bacterial and viral pathogens associated with PPI use. The long-term goal of the proposed study is to develop a screening tool to identify PPI-associated changes in microflora that enable clinicians to alter acid suppression therapy before infections develop. The specific aims of the proposed study are: (1) to compare the abundance and diversity of gastric, oropharyngeal, and fecal microflora in children with GERD who are taking PPIs with those in untreated children with GERD and healthy control subjects; (2) to determine, within individuals, the longitudinal impact of PPI use on the abundance and diversity of gastric, oropharyngeal, and fecal microflora; and (3) to determine whether specific changes in oropharyngeal and fecal microflora in patients who are taking PPIs are associated with increased risk of pneumonia and gastroenteritis and to identify potential viral and bacterial pathogens associated with PPI use in children. The proposed research is significant because it will advance scientific understanding of the increased infection risk associated with one of the most commonly prescribed classes of medications in a vulnerable pediatric population. Ultimately, this knowledge can be used to develop new therapeutic algorithms for PPI use in children that reduce the risk of infectious complications.